Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[C:12](#[N:16])[C:13]([CH3:15])=[CH2:14].C>CCCCCC.C(O)C>[NH2:16][C:12]1[CH:13]([CH3:15])[CH2:14][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[N:11]=1
Reactant: NNc1cccc(F)c1
Reactant: C=C(C)C#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CCCCCC
Product: CC1CN(c2cccc(F)c2)N=C1N

Procedure:
A 1.38 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 8.1 g. of m-fluorophenylhydrazine hydrochloride is added followed by 3.9 g. of methacrylonitrile. The reaction mixture is refluxed for 5 hours, then is evaporated to dryness in vacuo. Water is added to give a dark semi-solid precipitate. The aqueous is decanted then more water is added and the solid is collected by filtration. The solid is dissolved in dichloromethane and the solution is passed through a short column of a hydrous magnesium silicate. The effluent is evaporated to give an oil. The oil is dissolved in hexane, treated with activated charcoal and filtered and evaporated to give a solid. The solid is recrystallized from hexane to give 0.65 g. of the desired product as light orange prisms, m.p. 78°-80° C.
Reaction SMILES: C(OC1C=C(OC(C)C)C(F)=C(C(C2N(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=C(C3C=CC=CC=3C(F)(F)F)N=2)NC2C=CC(C3N=C(C)ON=3)=CC=2)C=1)C.Br[C:64]1[N:65]=[C:66]([CH:88]([C:102]2[CH:107]=[C:106]([O:108][CH2:109][CH3:110])[CH:105]=[C:104]([O:111][CH:112]([CH3:114])[CH3:113])[C:103]=2[F:115])[NH:89][C:90]2[CH:95]=[CH:94][C:93]([C:96]3[N:100]=[C:99]([CH3:101])[O:98][N:97]=3)=[CH:92][CH:91]=2)[N:67]([C:69]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:68]=1.[NH:116]1[CH:120]=[C:119](B(O)O)[CH:118]=[N:117]1>>[NH:116]1[CH:120]=[C:119]([C:64]2[N:65]=[C:66]([CH:88]([C:102]3[CH:107]=[C:106]([O:108][CH2:109][CH3:110])[CH:105]=[C:104]([O:111][CH:112]([CH3:114])[CH3:113])[C:103]=3[F:115])[NH:89][C:90]3[CH:91]=[CH:92][C:93]([C:96]4[N:100]=[C:99]([CH3:101])[O:98][N:97]=4)=[CH:94][CH:95]=3)[N:67]([C:69]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:82]3[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=3)[CH:68]=2)[CH:118]=[N:117]1
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: OB(O)c1cn[nH]c1
Agent: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(F)(F)F)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3cn[nH]c3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 20 %

Procedure:
According to the procedure for the preparation of Intermediate 77.1, Intermediate 66.3 was coupled with 1H-pyrazol-4-ylboronic acid. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes, gradient) to afford 30 mg (20%) of Intermediate 237.1.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1O)O.[CH3:10][C@H:11]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:12][CH2:13][CH2:14][C@H:15]([CH2:17][CH2:18][CH2:19][C@@:20]1([CH3:31])[O:25][C:24]2[CH:26]=[CH:27][C:28](O)=C[C:23]=2[CH2:22][CH2:21]1)[CH3:16].[CH2:38]([OH:40])[CH3:39]>>[CH3:28][C:27]1[C:38]([OH:40])=[CH:39][C:23]2[CH2:22][CH2:21][C@:20]([CH2:19][CH2:18][CH2:17][C@@H:15]([CH2:14][CH2:13][CH2:12][C@@H:11]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])[CH3:10])[CH3:16])([CH3:31])[O:25][C:24]=2[C:26]=1[CH3:1].[CH3:9][C:8]1[C:38]2[O:40][C@@:20]([CH2:19][CH2:18][CH2:17][C@@H:15]([CH2:14][CH2:13][CH2:12][C@@H:11]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])[CH3:10])[CH3:16])([CH3:31])[CH2:21][CH2:22][C:39]=2[C:3]([CH3:1])=[C:5]([OH:6])[CH:7]=1
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@]1(C)CCc2cc(O)ccc2O1
Reactant: CCO
Reactant: Oc1cccc(O)c1O
Product: Cc1c(O)cc2c(c1C)O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2
Product: Cc1cc(O)c(C)c2c1O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2

Procedure:
GMT expression vectors pMON36503 (FIG. 9), pMON36505 (FIG. 11) and pMON36506 (FIG. 12) are transformed into the soybean line A3244 using Agrobacterium mediated transformation. See, for example the methods described by Fraley et al., Bio/Technology 3:629-635 (1985) and Rogers et al., Methods Enzymol. 153: 253-277 (1987). Ten bulked seeds from the R1 generation are ground and the resulting soy meal is used for tocopherol analysis. Twenty five to forty mg of the soy meal is weighed into a 2 mL micro tube, and 500 μl 1% pyrogallol (Sigma Chemicals, St. Louis, Mo.) in ethanol containing 5 μg/mL tocol, is added to the tube. The sample is shaken twice for 45 seconds in a FASTPREP (Bio101/Savant) using speed 6.5. The extract is then filtered (Gelman PTFE acrodisc 0.2 μm, 13 mm syringe filters, Pall Gelman Laboratory Inc, Ann Arbor, Mich.) into an autosampler tube. HPLC is performed on a ZORBAX silica HPLC column, 4.6 mm×250 mm (5 μm) with a fluorescent detection using a Hewlett Packard HPLC (Agilent Technologies). Sample excitation is performed at 290 nm, and emission is monitored at 336 nm. Tocopherols are separated with a hexane methyl-t-butyl ether gradient using an injection volume of 20 μl, a flow rate of 1.5 ml/min, and a run time of 12 min (40° C.). Tocopherol concentration and composition is calculated based on standard curves for α, β, γ and δ-tocopherol using Chemstation software (Agilent Technologies, Palo Alto, Calif.). As shown in FIGS. 14-16, several lines from each construct completely or substantially converted δ and γ-tocopherol, leaving α and β-tocopherol as the only detectable tocopherol isomers.
Reaction SMILES: [CH3:1][Si:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:9]=1.[C:35]1([C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][N:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:44]3[CH:43]=[N:42][C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:46][CH:45]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(I)cnn12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 90 °C
Yield: 81.8 %

Procedure:
A mixture of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (751 mg, 1.22 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (444 mg, 1.58 mmol), PdCl2(dppf)CH2Cl2 (99.6 mg, 0.122 mmol), and K3PO4 (777 mg, 3.66 mmol) in dioxane/H2O (7/0.7 mL) was degassed and then heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.2 in 20% EtOAc/Hexanes) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a pale yellow solid (643 mg). HPLC-MS TR=3.12 min (UV 254 nm, 5 min method); mass calculated for formula C35H49N5O3Si2 643.3, observed LCMS m/z 644.2 (M+H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1C(O)C)[CH2:8]2.CC1(C)N([O])C(C)(C)CCC1.[C:25](O)(=[O:27])[CH3:26].C(O)(=O)C.IC1C=CC=CC=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[C:1]12([CH2:26][CH:25]=[O:27])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(=O)O
Reactant: CC(O)C1C2CC3CC(C2)CC1C3
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: O=CCC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
To a flask containing 2-adamantyl-1-ethanol (5 g, 27.7 mmol) in CH2Cl2 (28 mL) was added TEMPO (433 mg, 2.77 mmol) followed by iodobenzene diacetate (9.8 g, 30.5 mmol). The reaction was stirred 1 hour and then diluted with CH2Cl2 (100 mL). Saturated aqueous solution of Na2S2O3 (100 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organics were washed with saturated aqueous NaHCO3 (150 mL) and brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5% Et2O/pentanes) to provide the title compound, which was identical to the reported literature compound (see Luly et al. (1987) J. Org. Chem. 52: 1487).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23]OS(C)(=O)=O)[N:11]=1)=[O:9].C(Cl)Cl>O>[F:35][C:33]([F:36])([F:34])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:38])([F:37])[F:1])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23][NH:11][CH2:10][CH2:8][N:7]([CH3:29])[CH3:6])[N:11]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(COS(C)(=O)=O)ncc1-c1ccccc1Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNCc1ncc(-c2ccccc2Cl)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of 0.62 g (1.07 mmol) methanesulfonic acid 4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-5-(2-chloro-phenyl)-pyrimidin-2-ylmethyl ester in 10 ml CH2Cl2 0.29 ml (2.66 mmol) 2-dimethylyminoethylamine were added. The reaction mixture was stirred for 16 hrs. at RT and than poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.22 g (36%) 5-(2-chloro-phenyl)-2-[(2-dimethylamino-ethylamino)-methyl]-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil, MS (ISP): 574.1 (M+H+).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][CH:4]([CH3:10])[C:5](=O)[CH2:6][C:7]#[N:8].S(O)(O)(=O)=O.[NH2:16]O>O.C(O)C>[CH:4]([C:5]1[CH:6]=[C:7]([NH2:8])[O:1][N:16]=1)([CH3:10])[CH3:3]
Reactant: [OH-]
Reactant: NO
Reactant: CC(C)C(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(N)on1
Temperature: 80 °C
Yield: 78 %

Procedure:
To a stirred solution of sodium hydroxide (238 mg, 5.95 mmol) and 4-methyl-3-oxopentanenitrile from the previous step (600 mg, 5.41 mmol) in a mixture of water (5 mL) and ethanol (5 mL), was added hydroxylamine sulfate (977 mg, 5.95 mmol). The reaction mixture was adjusted to pH 7.5 with aqueous 1N sodium hydroxide solution, then heated to 80° C. for 15 h. After cooling to room temperature the solvent was removed under reduced pressure. The resulting solid was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4, then concentrated under reduced pressure to afford 3-isopropylisoxazol-5-amine as a cream solid (530 mg, 78%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.00 (s, 1H), 4.39 (brs, 2H), 2.89 (septet, J=6 Hz, 1H), 1.23 (d, J=6 Hz, 6H); LC-MS (ESI) m/z 127 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:28])([F:27])[C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:17]1[CH2:18][C@H:13]([C:12]([F:28])([F:27])[F:11])[CH2:14][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:16]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 4-chloro-3-nitropyridine (580 mg, 3.6 mmol), tert-butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (800 mg, 3 mmol), isopropyl alcohol (5.0 mL) and DIPEA (1.0 mL, 6.0 mmol) was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using CombiFlash® apparatus eluting with 50-100% EtOAc/hexanes. The purification gave 1.0 g (80% yield) of the sub-title compound as a yellow solid. LCMS calc. for C16H22F3N4O4(M+H)+: m/z=: 391.2. found: 391.1.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.N[C:46]1[CH:47]=[N:48][CH:49]=CC=1.N[C:53]1C=CC=C[CH:54]=1>>[CH:6]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:49]=[N:48][CH:47]=[CH:46][CH:30]=5)=[O:27])=[CH:21][CH:20]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:8]([CH2:53][CH2:54]1)[CH2:9][O:12][CH2:5]2
Reactant: Nc1cccnc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccccc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4cccnc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 3-aminopyridine as the aniline component. (49%, MS=471.4 (M+H))
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].C(Cl)Cl.CO>C(#N)C>[Cl:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C(Cl)CCCCl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)CCCCl)c4c(c23)C1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 4 mL of acetonitrile was stirred at 20° C. 68 μL of 4-chlorobutyryl chloride were added. The mixture was magnetically stirred at 20° C. during 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 70 mg (yield: 53%) of the desired product (formula below) as an orange powder
Reaction SMILES: [O:1]=[C:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:17][Si:18]([CH3:21])([CH3:20])Cl.N12CCCCC1C=NCCC2>C(OCC)C>[C:11]1([CH:10]=[CH:9][C:2]([O:1][Si:18]([CH3:21])([CH3:20])[CH3:17])=[CH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CCC(=O)/C=C/c1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: C1=NCCCN2CCCCC12
Solvent: CCOCC
Product: COC(=O)CC=C(C=Cc1ccccc1)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 g of the product of Step B, 45 ml of diethyl ether and 2.2 ml of trimethylchlorosilane were mixed together and after the mixture was cooled to 0° C., then 2.5 ml of 1,5-diaza-5-bicyclo-[5,4,0]-undecene (DBU) and 20 ml of diethyl ether were added. The mixture was stirred while allowing the temperature to rise to 20° to 21° C. for one hour. After filtration, the ether was evaporated off to obtain 4.2 g of the desired product which was used as is in the following step.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[N:17]1([C:7]([CH:4]2[S:3][C:2]([Cl:1])=[N:6][CH2:5]2)=[O:9])[CH2:20][CH2:19][CH2:18]1
Reactant: C1CNC1
Reactant: O=C(O)c1cnc(Cl)s1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(C1CN=C(Cl)S1)N1CCC1
Reaction time: 16 h

Procedure:
To a solution of 2-chlorothiazole-5-carboxylic acid (815 mg, 5 mmol) in dichloromethane (10 mL) was slowly added oxalyl chloride (0.53 mL, 6 mmol) and then N,N dimethylformamide (1 drop) with stirring. The mixture was stirred for 16 hours, following which the organics were removed in vacuo, and the residues azeotroped with toluene (100 ml). The crude material was dissolved in dichloromethane (10 mL) and slowly added to a stirred suspension of azetidine hydrochloride (560 mg, 6 mmol) and triethylamine (2.5 mL, 18 mmol) in dichloromethane (25 mL). The mixture was stirred at ambient temperature for 2 hours before the organics were removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and water (25 mL), the organic layer washed with brine (25 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica with 40% ethyl acetate in iso-hexane as eluant to give 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazoline. 1H NMR δ (CDCl3): 2.4 (m, 2H), 4.1-4.4 (m, 4H), 4.55 (m, 1H), 7.2 (s, 1H) and 7.75 (s, 1H); m/z 203 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=[O:59])[CH2:34][C:35]([O:37][C@H:38]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:39]([OH:52])([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:36])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]([OH:59])[CH2:34][C:35]([O:37][C@H:38]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:39]([OH:52])([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:36])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)CC(=O)O[C@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)CC(=O)O[C@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 940.6 %

Procedure:
A solution of 5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-oxo-1-pentanoic acid, (R)-2-hydroxy-1,2,2-triphenylethyl ester (0.1 g, 0.127 mmol., 7) in 6 ml of THF/MeOH (1:2, v/v) was cooled to −78° C. To this solution was added sodium borohydride (20 mg) in two portions over a period of 0.5 h. The resulting reaction mixture was stirred at −78° C. for an additional 1 hour under nitrogen and then quenched with aqueous saturated NH4Cl solution and extracted with dichloromethane (10 mL×2). The combined dichloromethane layers were washed with brine (5 mL×2), dried (Na2SO4) and evaporated to give a white crystalline solid (0.94 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1OC)[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]1([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:5]1[C:4](=[O:22])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]1[CH2:12][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1-c1ccccc1
Yield: 168.3 %

Procedure:
Prepared according to Procedure C using Intermediate 21 (400 mg, 1.05 mmol), 6-mercapto-purine monohydrate (196 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was chromatographed in MeOH/CH2Cl2 and subsequently recrystallized from EtOH to provide 439 mg of a pale yellow crystalline solid (84%), mp 222.0-222.5° C. (dec). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.55 (s, 1H); 8.45 (s, 1H); 7.73 (t, J=8.0 Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.50-7.59 (m, 4H); 7.41-7.48 (m, 1H); 7.25-7.38 (m, 5H); 4.41 (d, J=16 Hz, 1H); 4.16 (d, J=16 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 157.0, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134.1, 133.3, 131.5, 130.5, 130.3, 130.1, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ES): m/z 497.0 (M+). Anal. calcd. for C26H17ClN6OS: C, 62.84; H, 3.45; Cl, 7.13; N, 16.91; S, 6.45. Found: C, 62.60; H, 3.47; Cl, 7.15; N, 16.65; S, 6.41.
Reaction SMILES: [Na+].[I-:2].CN[C@@H]1CCCC[C@H]1NC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(O)CCCC.CCCCC[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(OCC)(=O)C.[Cu]I>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[I:2][C:36]1[CH:35]=[CH:34][C:33]([CH3:32])=[CH:38][CH:37]=1
Reactant: [I-]
Reactant: CCCCCCCCCCCC
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCO
Solvent: CCOC(C)=O
Solvent: Cc1ccc(Cl)cc1
Product: Cc1ccc(I)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
A Schlenk tube was charged with CuI (19.5 mg, 0.102 mmol, 5.0 mol %), NaI (450 mg, 3.00 mmol), evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (31.5 μL, 0.200 mmol, 10 mol %), 4-chlorotoluene (237 μL, 2.00 mmol), and n-pentanol (0.50 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 24 h. The resulting dark green-gray suspension was allowed to reach room temperature. Ethyl acetate (3 mL) and dodecane (internal GC standard, 460 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 35% conversion of 4-chlorotoluene and 33% yield of 4-iodotoluene.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH3:19][C:20]([CH3:24])=[CH:21][CH:22]=O>N1C=CC=CC=1.CO.C(Cl)(Cl)Cl>[CH3:19][C:20]1([CH3:24])[O:12][C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH:22]=[CH:21]1
Reactant: CC(C)=CC=O
Reactant: Oc1cc(O)c2ccccc2n1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC1(C)C=Cc2c(c3ccccc3[nH]c2=O)O1
Reaction time: 12 h
Yield: 63.9 %

Procedure:
To a boiling solution of 2,4-dihydroxy quinoline (5.0 g, 31 mmol) in pyridine (300 ml) under argon was added anhydrous magnesium sulfate (20 g) followed by 3-methyl-2-butenal (2.6 g, 31.0 mmole). The reaction was heated under reflux for 16 hours. After 12 hours, more 3-methyl-2-butenal (1.3 g, 15.5 mmol) was added and the reaction was heated under reflux for 16 more hours. The reaction was diluted with 10% methanol in chloroform (200 ml) and filtered while hot. The solid was washed with hot solvent (10% methanol in chloroform) and the filtrate was concentrated in vacuo and coevaporated with toluene. The resulting solid was triturated with isopropyl ether to give the title A compound (4.5 g), m.p. 174° C.-177° C.: 1H NMR (DMSO-d6 /CDCl3) ppm: δ7.7 (d, 1H, J =8.0 Hz), 7.4 (d, 1H, J = 9.0 Hz), 7.2 (d, 1H, J =8.0 Hz), 7.1 (dd, 1H, J =7 & 8 Hz), 6.5 (d, 1H, J =8.0 Hz), 5.5 (d, 1H, J =9.0 Hz), 3.3 (s, 1H), 1.34 (2 s, 6H); 13C NMR (DMSO-d6 /CDCl3) ppm: 160.8, 158.7, 136.5, 128.9, 120.9, 120.2, 119.7, 115.0, 113.6, 113.4, 103.7, 76.7, 26.0.